Crixivan

"If you think you are at risk of getting HIV, ask your health care provider if PrEP is right for you. Along with other prevention methods like condoms, PrEP can offer good protection against HIV if taken every day.

Crixivan

WARNINGS

ALERT: Find out about medicines
that should NOT be taken with CRIXIVAN. This statement is included on the
product's bottle label.

Nephrolithiasis/Urolithiasis

Nephrolithiasis/urolithiasis
has occurred with CRIXIVAN therapy. The cumulative frequency of nephrolithiasis
is substantially higher in pediatric patients (29%) than in adult patients
(12.4%; range across individual trials: 4.7% to 34.4%). The cumulative
frequency of nephrolithiasis events increases with increasing exposure to
CRIXIVAN; however, the risk over time remains relatively constant. In some
cases, nephrolithiasis/urolithiasis has been associated with renal
insufficiency or acute renal failure, pyelonephritis with or without
bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur,
(including flank pain, with or without hematuria or microscopic hematuria),
temporary interruption (e.g., 13 days) or discontinuation of therapy may be
considered. Adequate hydration is recommended in all patients treated with
CRIXIVAN. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION, Nephrolithiasis/Urolithiasis.)

Hemolytic Anemia

Acute hemolytic anemia,
including cases resulting in death, has been reported in patients treated with
CRIXIVAN. Once a diagnosis is apparent, appropriate measures for the treatment
of hemolyticanemia should be instituted, including discontinuation of CRIXIVAN.

Hepatitis

Hepatitis including cases resulting in hepatic failure
and death has been reported in patients treated with CRIXIVAN. Because the
majority of these patients had confounding medical conditions and/or were
receiving concomitant therapy(ies), a causal relationship between CRIXIVAN and
these events has not been established.

Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing
diabetes mellitus and hyperglycemia have been reported during post-marketing
surveillance in HIV-infected patients receiving protease inhibitor therapy.
Some patients required either initiation or dose adjustments of insulin or oral
hypoglycemic agents for treatment of these events. In some cases, diabetic
ketoacidosis has occurred. In those patients who discontinued protease
inhibitor therapy, hyperglycemia persisted in some cases. Because these events
have been reported voluntarily during clinical practice, estimates of frequency
cannot be made and a causal relationship between protease inhibitor therapy and
these events has not been established.

Drug Interactions

Concomitant use of CRIXIVAN with lovastatin or
simvastatin is contraindicated due to an increased risk of myopathy including
rhabdomyolysis. Caution should be exercised if CRIXIVAN is used concurrently
with atorvastatin or rosuvastatin. Titrate the atorvastatin and rosuvastatin
doses carefully and use the lowest necessary dose with CRIXIVAN. (See
PRECAUTIONS: DRUG INTERACTIONS.)

Midazolam is extensively metabolized by CYP3A4.
Co-administration with CRIXIVAN with or without ritonavir may cause a large
increase in the concentration of this benzodiazepine. No drug interaction study
has been performed for the co-administration of CRIXIVAN with benzodiazepines.
Based on data from other CYP3A4 inhibitors, plasma concentrations of midazolam
are expected to be significantly higher when midazolam is given orally.
Therefore CRIXIVAN should not be co-administered with orally administered
midazolam (see CONTRAINDICATIONS), whereas caution should be used with
coadministration of CRIXIVAN and parenteral midazolam. Data from concomitant
use of parenteral midazolam with other protease inhibitors suggest a possible
3-4 fold increase in midazolam plasma levels. If CRIXIVAN with or without
ritonavir is co-administered with parenteral midazolam, it should be done in a
setting which ensures close clinical monitoring and appropriate medical
management in case of respiratory depression and/or prolonged sedation. Dosage
reduction for midazolam should be considered, especially if more than a single
dose of midazolam is administered.

Particular caution should be used when prescribing
sildenafil, tadalafil, or vardenafil in patients receiving indinavir.
Coadministration of CRIXIVAN with these medications is expected to
substantially increase plasma concentrations of sildenafil, tadalafil, and
vardenafil and may result in an increase in adverse events, including
hypotension, visual changes, and priapism, which have been associated with
sildenafil, tadalafil, and vardenafil (see CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONSand PATIENT INFORMATION, and the
manufacturer's complete prescribing information for sildenafil, tadalafil, or
vardenafil).

Concomitant use of CRIXIVAN and St. John's wort (Hypericum
perforatum) or products containing St. John's wort is not recommended.
Coadministration of CRIXIVAN and St. John's wort has been shown to
substantially decrease indinavir concentrations (see CLINICAL PHARMACOLOGY,
DRUG INTERACTIONS) and may lead to loss of virologic response and
possible resistance to CRIXIVAN or to the class of protease inhibitors.

PRECAUTIONS

General

Indirect hyperbilirubinemia has occurred frequently
during treatment with CRIXIVAN and has infrequently been associated with
increases in serum transaminases (see also ADVERSE REACTIONS, Clinical
Trials and Post-Marketing Experience). It is not known whether
CRIXIVAN will exacerbate the physiologic hyperbilirubinemia seen in neonates.
(See Pregnancy.)

Tubulointerstitial Nephritis

Reports of tubulointerstitial nephritis with medullary
calcification and corticalatrophy have been observed in patients with
asymptomatic severe leukocyturia ( > 100 cells/ high power field). Patients
with asymptomatic severe leukocyturia should be followed closely and monitored
frequently with urinalyses. Further diagnostic evaluation may be warranted, and
discontinuation of CRIXIVAN should be considered in all patients with severe
leukocyturia.

Autoimmune disorders (such as Graves' disease,
polymyositis, and Guillain-Barré syndrome) have also been reported to occur in
the setting of immune reconstitution; however, the time to onset is more
variable, and can occur many months after initiation of treatment.

Coexisting Conditions

Patients with hemophilia: There have been reports of
spontaneous bleeding in patients with hemophilia A and B treated with protease
inhibitors. In some patients, additional factor VIII was required. In many of
the reported cases, treatment with protease inhibitors was continued or
restarted. A causal relationship between protease inhibitor therapy and these
episodes has not been established. (See ADVERSE REACTIONS, Post-Marketing
Experience.)

Patients with renal insufficiency: Patients with renal
insufficiency have not been studied.

Fat Redistribution

Redistribution/accumulation of body fat including central
obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting,
facial wasting, breast enlargement, and “cushingoid appearance” have been
observed in patients receiving antiretroviral therapy. The mechanism and
long-term consequences of these events are currently unknown. A causal
relationship has not been established.

Information For Patients

A statement to patients and health care providers is
included on the product's bottle label. ALERT: Find out about medicines that
should NOT be taken with CRIXIVAN. A Patient Package Insert (PPI) for CRIXIVAN
is available for PATIENT INFORMATION.

CRIXIVAN is not a cure for HIV-1 infection and patients
may continue to experience illnesses associated with HIV-1 infection, including
opportunistic infections. Patients should remain under the care of a physician
when using CRIXIVAN.

Patients should be advised to avoid doing things that can
spread HIV-1 infection to others.

Do not share needles or other injection equipment.

Do not share personal items that can have blood or
body fluids on them, like toothbrushes and razor blades.

Do not have any kind of sex without protection. Always
practice safe sex by using a latex or polyurethane condom to lower the chance
of sexual contact with semen, vaginal secretions, or blood.

Do not breastfeed. We do not know if CRIXIVAN can
be passed to your baby in your breast milk and whether it could harm your baby.
Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to
the baby in the breast milk.

Patients should be advised to remain under the care of a
physician when using CRIXIVAN and should not modify or discontinue treatment
without first consulting the physician. Therefore, if a dose is missed,
patients should take the next dose at the regularly scheduled time and should
not double this dose. Therapy with CRIXIVAN should be initiated and maintained
at the recommended dosage.

CRIXIVAN may interact with some drugs; therefore,
patients should be advised to report to their doctor the use of any other
prescription, non-prescription medication or herbal products, particularly St.
John's wort.

For optimal absorption, CRIXIVAN should be administered
without food but with water 1 hour before or 2 hours after a meal.
Alternatively, CRIXIVAN may be administered with other liquids such as skim
milk, juice, coffee, or tea, or with a light meal, e.g., dry toast with jelly,
juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar
(see CLINICAL PHARMACOLOGY, Effect of Food on Oral Absorption and
DOSAGE AND ADMINISTRATION). Ingestion of CRIXIVAN with a meal high in
calories, fat, and protein reduces the absorption of indinavir.

Patients receiving a phosphodiesterase type 5 (PDE5)
inhibitor (sildenafil, tadalafil, or vardenafil) should be advised that they
may be at an increased risk of PDE5 inhibitor-associated adverse events
including hypotension, visual changes, and priapism, and should promptly report
any symptoms to their doctors (see CONTRAINDICATIONS and WARNINGS: Drug Interactions).

Patients should be informed that redistribution or
accumulation of body fat may occur in patients receiving antiretroviral therapy
and that the cause and long-term health effects of these conditions are not
known at this time.

CRIXIVAN Capsules are sensitive to moisture. Patients
should be informed that CRIXIVAN should be stored and used in the original
container and the desiccant should remain in the bottle.

Carcinogenesis, Mutagenesis,
Impairment Of Fertility

Carcinogenicity studies were
conducted in mice and rats. In mice, no increased incidence of any tumor type
was observed. The highest dose tested in rats was 640 mg/kg/day; at this dose a
statistically significant increased incidence of thyroid adenomas was seen only
in male rats. At that dose, daily systemic exposure in rats was approximately
1.3 times higher than daily systemic exposure in humans. No evidence of
mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis
(Ames) tests, in vitro alkaline elution assays for DNA breakage, in vitro and in
vivo chromosomal aberration studies, and in vitro mammalian cell mutagenesis
assays. No treatment-related effects on mating, fertility, or embryo survival
were seen in female rats and no treatment-related effects on mating performance
were seen in male rats at doses providing systemic exposure comparable to or
slightly higher than that with the clinical dose. In addition, no
treatment-related effects were observed in fecundity or fertility of untreated
females mated to treated males.

Pregnancy

Pregnancy Category C

Developmental toxicity studies
were performed in rabbits (at doses up to 240 mg/kg/day), dogs (at doses up to
80 mg/kg/day), and rats (at doses up to 640 mg/kg/day). The highest doses in
these studies produced systemic exposures in these species comparable to or
slightly greater than human exposure. No treatment-related external, visceral,
or skeletal changes were observed in rabbits or dogs. No treatment-related
external or visceral changes were observed in rats. Treatment-related increases
over controls in the incidence of supernumerary ribs (at exposures at or below
those in humans) and of cervical ribs (at exposures comparable to or slightly
greater than those in humans) were seen in rats. In all three species, no
treatment-related effects on embryonic/fetal survival or fetal weights were
observed.

In rabbits, at a maternal dose
of 240 mg/kg/day, no drug was detected in fetal plasma 1 hour after dosing.
Fetal plasma drug levels 2 hours after dosing were approximately 3% of maternal
plasma drug levels. In dogs, at a maternal dose of 80 mg/kg/day, fetal plasma
drug levels were approximately 50% of maternal plasma drug levels both 1 and 2
hours after dosing. In rats, at maternal doses of 40 and 640 mg/kg/day, fetal
plasma drug levels were approximately 10 to 15% and 10 to 20% of maternal
plasma drug levels 1 and 2 hours after dosing, respectively.

Indinavir was administered to
Rhesus monkeys during the third trimester of pregnancy (at doses up to 160
mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg
twice daily). When administered to neonates, indinavir caused an exacerbation
of the transient physiologic hyperbilirubinemia seen in this species after
birth; serum bilirubin values were approximately fourfold above controls at 160
mg/kg twice daily. A similar exacerbation did not occur in neonates after in
utero exposure to indinavir during the third trimester of pregnancy. In Rhesus
monkeys, fetal plasma drug levels were approximately 1 to 2% of maternal plasma
drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg
twice daily.

Hyperbilirubinemia has occurred
during treatment with CRIXIVAN (see PRECAUTIONS and ADVERSE REACTIONS).
It is unknown whether CRIXIVAN administered to the mother in the perinatal
period will exacerbate physiologic hyperbilirubinemia in neonates.

There are no adequate and
well-controlled studies in pregnant patients. CRIXIVAN should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.

A CRIXIVAN dose of 800 mg every
8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a
day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of
gestation at enrollment (study PACTG 358). Given the substantially lower
antepartum exposures observed and the limited data in this patient population,
indinavir use is not recommended in HIV-infected pregnant patients (see
CLINICAL PHARMACOLOGY, Pregnant Patients).

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant patients exposed
to CRIXIVAN, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling 1800-258-4263.

Nursing Mothers

Studies in lactating rats have demonstrated that
indinavir is excreted in milk. Although it is not known whether CRIXIVAN is
excreted in human milk, there exists the potential for adverse effects from
indinavir in nursing infants. Mothers should be instructed to discontinue
nursing if they are receiving CRIXIVAN. This is consistent with the
recommendation by the U.S. Public Health Service Centers for Disease Control
and Prevention that HIV-infected mothers not breast-feed their infants to avoid
risking postnatal transmission of HIV.

Pediatric Use

The optimal dosing regimen for use of indinavir in
pediatric patients has not been established. A dose of 500 mg/m² every eight
hours has been studied in uncontrolled studies of 70 children, 3 to 18 years of
age. The pharmacokinetic profiles of indinavir at this dose were not comparable
to profiles previously observed in adults receiving the recommended dose (see CLINICAL
PHARMACOLOGY, Pediatric). Although viral suppression was observed in
some of the 32 children who were followed on this regimen through 24 weeks, a
substantially higher rate of nephrolithiasis was reported when compared to
adult historical data (see WARNINGS, Nephrolithiasis/Urolithiasis).
Physicians considering the use of indinavir in pediatric patients without other
protease inhibitor options should be aware of the limited data available in
this population and the increased risk of nephrolithiasis.

Geriatric Use

Clinical studies of CRIXIVAN did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. In general, dose selection for an elderly
patient should be cautious, reflecting the greater frequency of decreased
hepatic, renal or cardiac function and of concomitant disease or other drug
therapy.

Last reviewed on RxList: 8/7/2014
This monograph has been modified to include the generic and brand name in many instances.